Breast cancer remains the second highest cause of cancer-related deaths among women despite significant improvements in diagnosis and treatments. Women with aggressive triple-negative breast cancer (TNBC) face poor patient outcomes and lack effective targeted therapies. Despite extensive efforts to characterize this subtype, the oncogenic drivers of TNBC remain elusive and pose a challenge that must be overcome. Widespread chromosomal instability is a characteristic feature of TNBC, making it difficult to decipher between genes that drive cancer development from those that play a bystander role. Little is known about what gives rise to the extensive genomic instability of TNBC, and presents a major deficit in our scientific and clinical knowledge. To maintain genomic integrity, cells utilize a DNA damage response (DDR) mechanism that functions to sense damaged DNA, repair it efficiently and commit cells to death if the damage is irreparable. Activation of this system is critically important in suppressing the onset of malignancy. Occurrences of altered DDR have been observed in pre-malignant lesions as well as in malignant cells, but not in normal/healthy tissue, indicating that perturbations in this system may contribute to tumorigenesis and its associated genomic aberrations. Knowing how TNBC tumors are able to bypass or disrupt the DDR system will be critical to understanding their patterns of genomic instability, their phenotypic properties, and their therapeutic sensitivities. Thus, the gol of this proposal is to identify the drivers of genomic instability in TNBC, and to use these insighs to guide the development of personalized therapies for patients with this disease. In order to accurately distinguish driver genes from bystander genes we propose to create novel models of TNBC by inducing specific genetic alterations in mammary epithelial cells either in cell culture or in a mouse model. These genetically controlled model systems will enable us to determine causality of specific DDR mutations in breast cancer development and importantly, the genomic instability phenotype typical for TNBC. The insights gleaned from the proposed work may provide the means to determine the most effective treatment regimens, and to prevent over-treatment of patients where certain chemotherapies may not be effective. Support of this project will also advance the short- and long-term goals of an emerging young, female, minority scientist, Dr. Katerina Fagan-Solis. The tailored mentoring and training plan ensures research support, access to core facilities and equipment to enhance technical capabilities, and multiple opportunities to attend both scientific and career-focused workshops, seminars, national meetings, and frequent involvement with other prominent scientists to develop networking, presentation, and communication skills. Awarding this fellowship will be vital to the growth and success of Dr. Fagan-Solis as an independent researcher and scientist.